JPWO2008088008A1 - Gastrointestinal dysfunction prevention and / or treatment agent - Google Patents

Abstract

The present inventors conducted dedicated studies, and as a result discovered that propionic acid bacteria fermentation products have a preventive/therapeutic effect on functional gastrointestinal disorders in in vitro tests and tests using patients with irritable bowel syndrome, and completed the present invention. Specifically, the present inventors discovered, in in vitro tests, that the products have an effect of increasing the intestinal contraction frequency without changing the intestinal contractile force in a distal colon-specific manner. Moreover, effects of improving the defecation condition, general abdominal condition, and health-related QOL in patients with irritable bowel syndrome were also found. Furthermore, propionic acid bacteria fermentation products can be taken in large amounts. Therefore, the propionic acid bacteria fermentation products can be expected to have an effect of preventing/treating functional gastrointestinal disorders safely.

Description

  The present invention relates to a preventive and / or therapeutic agent for gastrointestinal dysfunction, a food for preventing and / or treating gastrointestinal dysfunction, and the use of a fermented propionic acid bacterium for producing them.

Functional gastrointestinal disorders (FGIDs) are a group of gastrointestinal diseases that do not have organic diseases (such as colorectal cancer, ulcerative colitis, Crohn's disease, and amoeba dysentery). Abnormalities such as gastrointestinal motility and sensory perception cause various symptoms such as abdominal pain, nausea, vomiting, abdominal bloating, and defecation abnormalities such as diarrhea and constipation.
FGIDs include a total of 25 diseases, including esophageal disease 6, gastroduodenal disease 3, intestinal disease 5, abdominal pain 2, biliary tract 2, rectal / anal 3, and childhood region 4, of which constipation is the main symptom, for example, Except for the pediatric field, there are two diseases: irritable bowel syndrome (IBS) and functional constipation (FC).
Although FGIDs have no impact on life prognosis, they have had a negative impact on society because they have caused a decline in quality of life (QOL) and an increase in medical expenses.
In the last few decades, research on organic diseases has progressed dramatically, and even malignant tumors have not been called incurable diseases. On the other hand, research on gastrointestinal dysfunction is still in the process of development, and the incidence of FGIDs is expected to increase further in the 21st century, which is called the stress society. This is a major issue in the future.

  Irritable bowel syndrome (IBS) in FGIDs is caused by a malfunction of the lower gastrointestinal tract, and its pathophysiology is known to be an abnormal movement of the intestinal tract, mainly the large intestine. Symptoms include abdominal pain and abdominal discomfort (characterized by relief from defecation), bowel movement abnormalities (diarrhea, constipation, mixed diarrhea / constipation), fecal abnormalities (mixed mucus, abnormal hardness) Abdominal fullness is observed. In the diarrhea type, the intestinal transit time is shortened, and in the constipation type, the intestinal transit time is prolonged. Although the site and contractility are different, intestinal hypermotility is observed in all cases. Comparing healthy subjects with IBS patients, it is said that there are abnormal reactions to stimuli such as stress and diet and cholinergic drugs. It is also said that there is a decrease in the perception threshold for dilation stimulation of the rectum and ileocecal part (Non-patent Document 1).

  Improve constipation symptoms include those that swell the stool with water to improve stool and create constipation (intensive laxative), or those that directly increase bowel movement, especially intestinal contractility (stimulation) Addictive laxatives) and the like are conventionally known. Stimulant laxatives have a strong defecation effect, but are not suitable for long-term use because they develop tolerance through continuous use. In addition, IBS treatment methods include a method of relieving abnormal intestinal convulsions with an anticholinergic agent, a method of assisting the movement of contents by stool moisture adjustment and gelation with dietary fiber, etc., and stress with an anxiolytic agent. Methods for reducing symptoms are known. However, many anticholinergic drugs are designated as powerful drugs (trancolons, etc.). In addition, polycarbophil calcium preparations that regulate water content by gelling are also contraindicated in patients with acute abdominal diseases, hypercalcemia, renal failure, kidney stones, etc. Development of preventive or therapeutic agents is expected.

The fermented product by Propionibacterium freudenreichii is known as a propionic acid bacteria fermented product, and has been reported to be effective for the growth of various bifidobacteria and the improvement of inflammatory bowel disease ( Patent Document 1). In addition, 1,4-dihydroxy-2-naphthoic acid (DHNA), which is one of the components of the propionic acid bacteria fermented product, also has a bifidobacteria growth promoting action (Patent Document 2), a metabolic bone disease preventive and therapeutic action ( Patent Document 3), which has been found to have an action to reduce abdominal discomfort symptoms (Patent Document 4) seen when ingesting milk intolerant to milk.
International Publication No. 2005/099725 Pamphlet JP-A-8-98677 International Publication No. 01/28547 Pamphlet International Publication No. 03/016544 Pamphlet Supervised by Hiroo Imura et al., “Latest University of Medicine, Progress 8, Gastrointestinal Disease”, published by Nakayama Shoten, pp. 51, 1997

  An object of the present invention is to provide a highly safe agent for preventing and / or treating gastrointestinal dysfunction.

  As a result of intensive studies, the present inventors have found that fermented propionic acid bacteria have a preventive / therapeutic effect on gastrointestinal dysfunction in in vitro tests and tests using irritable bowel syndrome patients. Completed.

  Specifically, in an in vitro test, it was found that it has an action to increase the frequency of contraction of the intestine without changing the intestinal contraction force in the distal large intestine. We found an improvement effect on general abdominal condition and health-related quality of life. Moreover, a large amount of the propionic acid bacteria fermented product can be ingested. Therefore, the propionic acid bacteria fermented product can be expected to safely prevent / treat gastrointestinal dysfunction.

That is, the present invention
[1] A preventive and / or therapeutic agent for gastrointestinal dysfunction comprising a fermented propionic acid bacterium and / or a processed product thereof as an active ingredient,
[2] The agent for preventing and / or treating gastrointestinal dysfunction according to [1], wherein the propionic acid bacterium belongs to the genus Propionibacterium,
[3] The preventive and / or therapeutic agent for gastrointestinal dysfunction according to [2], wherein the bacterium belonging to the genus Propionibacterium is Propionibacterium freudenreichii,
[4] The agent for preventing and / or treating gastrointestinal dysfunction according to [3], wherein Propionibacterium freudenreichii is Propionibacterium freudenreichii ET-3 (FERM BP-8115),
[5] The agent for preventing and / or treating gastrointestinal dysfunction according to any one of [1] to [4], wherein the propionic acid bacteria fermented product is a propionic acid bacteria whey fermented product.
[6] The gastrointestinal tract according to any one of [1] to [5], wherein the gastrointestinal dysfunction is one or a combination of a group consisting of irritable bowel syndrome or functional constipation Dysfunction prevention and / or treatment agent,
[7] A food for preventing and / or treating gastrointestinal dysfunction comprising the agent for preventing and / or treating gastrointestinal dysfunction according to any one of [1] to [6],
[8] Use of a fermentation product of propionic acid bacteria for producing a preventive and / or therapeutic agent for gastrointestinal dysfunction according to any one of [1] to [6],
[9] Use of a fermentation product of propionic acid bacteria for the production of a food for preventing and / or treating gastrointestinal dysfunction according to [7],
[10] A method for preventing and / or treating gastrointestinal dysfunction, comprising administering a fermentation product of propionic acid bacteria and / or a processed product thereof,
Consists of.

  The agent for preventing and / or treating gastrointestinal dysfunction according to the present invention can safely prevent and / or treat gastrointestinal dysfunction, particularly irritable bowel syndrome, spastic constipation or functional constipation.

The representative chart at the time of measuring the effect | action with respect to intestinal smooth muscle of a propionic acid bacteria whey fermented product is shown. In Example 1, it is an example of the measurement chart observed when a propionic acid bacterium whey fermented material is added to the distal large intestine. This is a questionnaire about the status of defecation. Used in Example 4. A questionnaire on general abdominal conditions. Used in Example 4. The result of the SF-36 questionnaire of Example 4 is shown. For each area score, the upper row compares before and after active intake, the lower row compares before and after placebo intake (score improved: Improve (shaded), no change: No change (□), exacerbation Was observed: Worsen (black square)) as a percentage of cases. The result of the SF-36 questionnaire of Example 4 is shown. The change in score of each region was calculated before and after ingestion, and the difference was evaluated before and after ingestion for each placebo (□) and active (black square). *: P <0.05 (Student's t-test)

  Hereinafter, the present invention will be described in detail. However, the present invention is not limited to the following preferred embodiments, and can be freely changed within the scope of the present invention.

  The propionic acid bacteria fermented product that is an active ingredient of the preventive and / or therapeutic agent for gastrointestinal dysfunction according to the present invention can be produced according to a known production method described in International Publication No. 03/016544 pamphlet or the like. . In the present specification, the “propionic acid bacteria fermentation product” refers to a culture itself obtained by fermentation with propionic acid bacteria. The agent for the prevention and / or treatment of gastrointestinal dysfunction according to the present invention includes the fermentation product of propionic acid bacteria and the processed product thereof, for example, the culture product (fermented product of propionic acid bacteria) removed by filtration, centrifugation, membrane separation or the like. Concentrate, paste, diluted or (freeze, heat, depressurize) the culture filtrate or culture supernatant obtained by fungi, the culture filtrate / culture supernatant or propionic acid bacteria fermentation product etc. Etc.) Dry products, or those obtained by sterilizing or sterilizing these products are included. In the present invention, in the preparation of the processed product, one or more of the above-described processing steps such as sterilization treatment such as filtration, centrifugation, membrane separation, precipitation, concentration, pasting, dilution, drying, sterilization, sterilization, etc. They can be used in combination.

  The medium used for the production of propionic acid bacteria fermentation products usually contains a nutrient source from which microorganisms can grow. Nutrient sources include whey, casein, skim milk powder, whey protein concentrate (WPC), whey protein isolate (WPI), yeast extract, soy extract, trypticase and other peptones, glucose, lactose and other sugars, and whey minerals Etc., or foods containing a large amount of these can be added. Alternatively, these enzyme-treated products may be added. In particular, it is preferable to use whey or an enzymatic degradation product thereof, but it is not limited to this example. In the present invention, a propionic acid bacteria fermented product using whey, WPC or WPI-derived whey-derived nutrients as a nutrient source is hereinafter referred to as a propionic acid whey fermented product.

  Examples of the enzyme used when enzymatically decomposing the nutrient source include one or a combination of protease and peptidase. Although the protease or peptidase to be used is not particularly limited, for example, the food grade protease includes endo-type protease, exo-type protease, exo-type peptidase / endo-type protease complex enzyme, and protease / peptidase complex enzyme. Endo-type proteases include, for example, chymosin (EC 3.4.23.4, Maxiren, modified yeast Kluyveromyces lactis origin, GIST-BROCADES NV), AlcalaseR (Bacillus licheniformis origin, Novo), Esperase (B. lentus origin, Novo), NeutraseR (B. subtilis origin, Novo), Protamex (bacterial origin, Novo), PTN6.0S (porcine pancreatic trypsin, Novo), etc., for example, flavorzyme ( Aspergillus oryzae origin, Novo). Other endo-type proteases include, for example, trypsin (CAS No. 9002-07-7, EC 3.4.21.4, bovine pancreas-derived, Product No. T8802, SIGMA), pepsin (CAS No. 9001-75-6, EC 3.4.4.1, derived from porcine gastric mucosa, SIGMA), chymotrypsin (Novo, Boehringer), protease N “Amano” G (derived from Bacillus subtilis; Amano Enzyme), biolase (derived from Bacillus subtilis; Nagase Sangyo), papain W-40 (Amano Enzyme) and exo-type protease include pancreatic carboxypeptidase, small intestinal brush border aminopeptidase, and the like. As the protease / peptidase complex enzyme, for example, protease A “Amano” G (derived from Aspergillus oryzae; Amano Enzyme), equine enzyme G (peptidase and protease, derived from Aspergillus oryzae; Amano Enzyme) can be used. The origin of the enzyme is not limited to the above description and may be derived from any of animals, plants and microorganisms, but those derived from Aspergillus oryzae are preferred. These enzymes do not mean a limited product name, origin, or manufacturer. In the practice of the present invention, the enzymes may be used alone or in combination of two or more. Suitable examples include protease A “Amano” G (derived from Aspergillus oryzae; Amano enzyme), but are not limited to this example. Moreover, when using combining the above-mentioned enzyme, each enzyme reaction may be simultaneous or may be performed separately.

  When the nutrient source is decomposed by an enzyme, the nutrient source as a raw material is dispersed and dissolved in water or hot water, and the enzyme is added. The pH at the start of enzymatic degradation, the enzymatic degradation time, and the enzyme reaction temperature are not particularly limited as long as the product of the present invention can be obtained, but if dare to mention, the pH at the start of enzymatic degradation is from 3.0 to 7.5, preferably from 4.5 to 7.0. Preferably it can carry out by 6.0-7.0. The enzymatic degradation time is 0.5 to 300 hours, preferably 1 to 20 hours, and more preferably 1 to 5 hours. The enzyme reaction temperature can be 20 to 57 ° C, preferably 30 to 52 ° C, more preferably 40 to 52 ° C.

  As a suitable example for preparing a medium for producing a propionic acid bacteria fermented product, whey powder (10 w / w%) and protease Amano A “Amano” G (0.07 w / w%, manufactured by Amano Enzyme) And then digested for 2 hours at 47 ° C (pH 6.6), then inactivated by heating at 85 ° C for 10 minutes, and then brewed yeast extract (0.10 w / w%, Asahi Beer) and ammonium sulfate (0.27 w / w%) can be added to adjust the pH to 6.7, followed by sterilization at 121 ° C. for 7 minutes, but is not limited to this example.

  The propionic acid bacteria used in the production of fermented propionic acid bacteria include Propionibacterium, Propionicimonas, Propioniferax, Propionimicrobium. ) Genus, Propionivibrio genus and the like, and although not particularly limited, bacteria belonging to the genus Propionibacterium are preferred. Examples of the genus Propionibacterium include Propionibacterium freudenreichii, Propionibacterium thoenii, Propionibacterium acidipropionici, Propionibacterium acidipropionici, Propionibacterium acidipropionici, Propionibacterium acidipropionici, Fungi for cheese such as Propionibacterium jensenii, Propionibacterium avidum, Propionibacterium acnes, Propionibacterium lymphophilum, Propionibacterium lymphophilum Propionibacterium granulosam, Propionibacterium arabinosum, Propionibacterium cyclohexanicum, Propionibacte rium innocuum, Propionibacterium intermediu, Propionibacterium pentosaceum, Propionibacterium peterssonii, Propionibacterium propionicum, Propionibacterium zeae, etc., among these, Propionibacterium freudenreichii (hereinafter also referred to as P. freudenreichii) is preferred, more preferably Propionibacterium frFOdenreichi or 12 Propionibacterium freudenreichii ATCC 6207, particularly Propionibacterium freudenreichii ET-3 (FERM BP-8115) is preferred.

The inventors deposited the Propionibacterium freudenreichii ET-3 strain at the Patent Organism Depositary, National Institute of Advanced Industrial Science and Technology. The contents specifying the deposit are described below.
(1) Depositary name: National Institute of Advanced Industrial Science and Technology, Patent Biological Depositary Center (2) Contact: Chuo 6th 1-1 1-1 Higashi 1-chome Tsukuba City, Ibaraki Prefecture 305-8566
(3) Accession number: FERM BP-8115
(4) Display for identification: ET-3
(5) Date of original deposit: August 9, 2001 (6) Date of transfer to deposit under the Budapest Treaty: July 11, 2002 The above Propionibacterium freudenreichii ET-3 was isolated from Emmental cheese. It is a Gram-positive short koji mold, negative for nitrate reduction, negative for indole production, negative for hydrogen sulfide production, and positive for lactose fermentation. Furthermore, it has the ability to produce DHNA.

  Moreover, the strain described as ATCC in the strain name indicates a reference strain obtained from the American Type Culture Collection, and the strain described as IFO in the strain name indicates a reference strain obtained from the Fermentation Research Institute.

  Next, this propionic acid bacterium is cultured in the medium. A known anaerobic or aerobic culture method can be used as the culture method, but an anaerobic or aerobic culture method using a liquid medium is preferably used. The pH at the start of fermentation, the fermentation time, and the fermentation temperature are not particularly limited as long as the agent for preventing and / or treating gastrointestinal dysfunction of the present invention can be obtained, but the pH at the start of fermentation is 3.0 to 7.5, preferably 5.0. -7.5, more preferably pH 5.5-7.0. The fermentation time is 0.5 to 200 hours, preferably 50 to 100 hours, more preferably 60 to 99 hours, and the fermentation temperature is 20 to 50 ° C, preferably 25 to 45 ° C, more preferably 30 to 40 ° C. it can. The culture solution thus obtained may be used immediately after culturing, but it is desirable that the culture solution is cooled (3 to 20 ° C., preferably about 10 ° C.) and stored for about 2 to 4 weeks before use. . As a preferred example, a culture medium sterilized at 121 ° C. for 7 minutes after being adjusted to pH 6.8 is inoculated with 0.01 to 2.5% of an activated culture solution of P. freudenreichii ET-3 (FERM BP-8115 strain), and is placed under a nitrogen atmosphere. A method of anaerobically culturing at ˜37 ° C. for 72 to 99 hours and obtaining this culture solution as a fermentation product of propionic acid bacteria is not limited to this example.

  For example, about 10 w / w% aqueous whey solution was decomposed with protease A “Amano” G (40 to 52 ° C., pH 6.0 to 7.0 for 1 to 5 hours), and a medium prepared by adding brewer's yeast extract and ammonium sulfate Propionibacterium freudenreichii ET-3 activation culture solution was inoculated in an amount of 0.01 to 2.5% and anaerobically cultured at 32 to 37 ° C in a nitrogen atmosphere for 72 to 99 hours to produce a propionic acid bacteria whey fermentation product. The bacterial concentration of ET-3 is about 0.5 to 50 × cfu / mL, the DHNA content is about 5 to 500 μg / mL, and the solid content is about 5 to 15 w / w%.

  Furthermore, the agent for preventing and / or treating gastrointestinal dysfunction according to the present invention can be obtained as it is, or as a soluble or insoluble fraction obtained by diluting the propionic acid bacterium fermentation product or its treated product with a solvent. As the solvent, water or a commonly used solvent, for example, alcohols, hydrocarbons, organic acids, organic bases, inorganic acids, inorganic bases, supercritical fluids and the like can be used alone or in combination.

  The agent for preventing and / or treating gastrointestinal dysfunction obtained as described above can be used as it is, and if necessary, this solution can be used as a solution concentrated or diluted by a known method. You can also Furthermore, this concentrated liquid can also be used as a dried product by a known method.

  The agent for preventing and / or treating gastrointestinal dysfunction of the present invention is useful as a composition effective for the prevention and / or treatment of gastrointestinal dysfunction. It has been confirmed in the Magnus method using rat intestinal smooth muscle and clinical trials targeting IBS patients.

  Irritable bowel syndrome (IBS) is caused by dysfunction of the lower gastrointestinal tract, and its pathophysiology is known to be an abnormal movement of the intestinal tract centering on the large intestine. Symptoms include abdominal pain and abdominal discomfort (characterized by relief from defecation), bowel movement abnormalities (diarrhea, constipation, mixed diarrhea / constipation), fecal abnormalities (mixed mucus, abnormal hardness) Abdominal fullness is observed. In the diarrhea type, the intestinal transit time is shortened, and in the constipation type, the intestinal transit time is prolonged. Although the site and contractility are different, intestinal motility is observed in all cases. Compared with healthy individuals and IBS patients, it is said that there are abnormal reactions to stress, dietary stimuli and cholinergic drugs. In addition, it is said that there is a decrease in the perception threshold for dilated stimulation of the rectum and ileocecal region (supervised by Hiroo Imura et al., “Latest University of Medicine, Progress 8, Gastrointestinal Disease”, published by Nakayama Shoten, pp. 51, 1997. Year).

  The large intestine is an organ responsible for functions such as absorption of moisture and electrolytes from the contents, maintenance of enteric bacteria, and defecation. In order to maintain these functions, it is important to propel the contents from the small intestine at an appropriate speed. For example, if the peristalsis of the upper colon occurs in IBS, absorption of water and the like from the contents becomes insufficient, resulting in symptoms of diarrhea. In addition, if the intestinal motility becomes irregular, the contents are hindered and constipation symptoms appear.

There are the following three types of functional constipation.
1. Habitual constipation (rectal constipation): Constipation that occurs due to decreased ability to feel constipation (rectal sensitivity), such as those who go out in the morning without having time to defecate.
2. Relaxing constipation: Constipation that is common in women after middle age and is caused by dull movement of the large intestine. Since the passage of intestinal contents is delayed, water absorption is increased.
3. Convulsive constipation: Constipation that causes stress in the large intestine and constricts the convulsions, so that the stool cannot pass smoothly through the large intestine, resulting in excessive water absorption and stool that is hard like a manure.

  Constipation drugs suitable for habitual constipation and flaccid constipation include those that swell the stool with moisture to improve stool and create constipation (bulge laxatives: dietary fiber preparations, salt laxatives, sugar laxatives, etc.) Directly intestinal motility, particularly those that enhance intestinal contractile force (irritant laxatives: diau, sennoside, picosulfate sodium, etc.) have been conventionally known. Stimulant laxatives have a strong defecation effect, but are not suitable for long-term use because they develop tolerance through continuous use. Spastic constipation is effective in releasing stress. In this case, even if the constipation medicine is taken, the stool at the exit is hard, so that it often suffers only from abdominal pain.

  In the irritable bowel syndrome constipation type, there are no organic abnormalities, and there is an abnormally high response due to stress, etc., so there is an increase in tension throughout the colon and a decrease in peristalsis, resulting in convulsive constipation (Masutoshi Mizutani, Akira Nakayama, Pathophysiology of large intestine motility and defecation function and constipation, clinical physiology series 6 intestine (Asakura Hitoshi et al.), Pp180-184, Nanedo, Tokyo, 1990). Therefore, it is thought that maintaining the colonic peristalsis movement normally is important for eliminating constipation.

  Conventional treatment methods for irritable bowel syndrome (constipation type, diarrhea type) are those that suppress abnormal convulsions of the intestine by anticholinergic drugs (roth extract, mepenzolate bromide, etc.), dietary fiber (polycarbophil calcium, etc.) ) And the like, which assist the movement of the contents by the moisture adjustment action and gelling action of the stool. Trimebutine maleate, used as a remedy for irritable bowel syndrome, acts directly on gastrointestinal smooth muscle and works in a suppressive manner in the state of increased gastrointestinal motility, and in an elevated state in an elevated state to regulate gastrointestinal motility. To do.

  On the other hand, the propionic acid bacteria fermented product of the present invention has been shown to increase the contraction frequency without enhancing the contraction force of the distal large intestine in the in vitro test described below. Furthermore, in the test using the irritable bowel syndrome constipation type patient described later, the propionic acid bacteria fermented product of the present invention has the effect of improving the patient's symptoms (defecation status, general abdominal condition) and health-related QOL. Indicated. Therefore, it can be said that the material is suitable for constipation type irritable bowel syndrome including spastic constipation.

  Irritable bowel syndrome is the most common disorder with symptoms of diarrhea, due to cooling the abdomen in the summer, drinking too much soft drinks, and worries and stress. Occur. Especially in today's stress society, many people are suffering from this disease. Possible mechanisms include increased secretion of water and electrolytes, impaired absorption of water from the intestinal tract, abnormalities in intestinal motility, and the like. Intestinal motility abnormalities may be caused by an increase in intestinal motility or by a decrease.

With regard to the small intestine, delaying the passage of the small intestine contents causes bacteria to grow in the small intestine and cause deconjugation of bile acids, which may cause fat and water absorption disorders and may cause diarrhea.
On the other hand, with regard to the large intestine, Munakata et al. Developed an endoscopic retrograde colon intubation method, in which two Teflon ^TM tubes were inserted into two locations, the ascending colon and the sigmoid colon. A macrochip is inserted to derive the pressure curve of the large intestine to observe the movement of the large intestine (Akihiro Munakata, Sumi Kawakami et al., Device and application of ileal tube placement, Gastroenterol Endsc, 21, 448-457 (1979)) . In patients with irritable bowel syndrome diarrhea at rest, the internal pressure is lower in the distal sigmoid than in the proximal ascending colon, and the pressure gradient of the intestinal tract is lower toward the anal side Intestinal contents are more likely to be pushed out after the rectum. This phenomenon is not improved by the administration of prostigmine, an anticholinergic drug (Sumi Kawakami, Irritable Bowel Syndrome, Autonomic Nervous System and Clinical Practice (Yuo Goto et al.), Pp. 276-303, Pharmaceutical Journal, Osaka Tokyo, 1982). Therefore, it is considered effective to increase the internal pressure of the sigmoid colon in the treatment or prevention of irritable bowel syndrome diarrhea type.

In addition, studies on sigmoid colon pressure are considered to be associated with decreased motor function in diarrhea (Merck Manual 17th Edition, Japanese), Section 03 Digestive system diseases Functional bowel disorder Irritable bowel Syndrome (IBS), http://merckmanual.banyu.co.jp/cgi-bin/disphtml.cgi?url=03/s032.html (January 15, 2008), Manyu Pharmaceutical Co., Ltd. website). Increasing the frequency of contraction of the sigmoid colon may be effective as one way to increase the reduced sigmoid intravascular pressure. The fermented propionic acid bacterium of the present invention has an action of increasing the contraction frequency for the distal colon. This indicates that the sigmoid colon with reduced function exerts a hyperkinetic action and increases the internal pressure, thereby increasing the pressure retrogradely to the proximal colon and improving the pressure gradient. . Therefore, the propionic acid bacteria fermented product of the present invention is considered to be effective against diarrhea-type irritable bowel syndrome.
In other words, suppression of intestinal hyperactivity does not necessarily suppress diarrhea, and maintenance of an appropriate pressure gradient may be an important factor.

  The agent for preventing and / or treating gastrointestinal dysfunction according to the present invention increased the contraction frequency without enhancing the contractile force of the intestinal smooth muscle of the distal large intestine in the in vitro test described below. The effect of increasing contraction frequency is not observed in the medium before inoculation with propionic acid bacteria, and it has been found that fermentation with propionic acid bacteria is important. On the other hand, the same test was performed on the proximal colon and the middle colon, but neither had any effect on the contractile force or contraction frequency of the intestinal smooth muscle. Therefore, in the preventive and / or therapeutic agent for gastrointestinal dysfunction according to the present invention, the proximal colon and the middle colon are moved to the anus while maintaining sufficient water absorption of the contents of the large intestine. It is expected that the contents are discharged from the large intestine, and the internal pressure is increased more than the proximal and middle colons. In other words, it is considered a useful material for diarrhea-type irritable bowel syndrome.

  The agent for preventing and / or treating gastrointestinal dysfunction according to the present invention is a composition effective for the prevention and / or treatment of gastrointestinal dysfunction, particularly gastrointestinal dysfunction, particularly irritable bowel syndrome (constipation type, diarrhea type, Application to mixed type), spastic constipation, functional constipation, etc. is possible. Moreover, it is possible to prepare a preventive and / or therapeutic agent for gastrointestinal dysfunction efficiently with a small number of steps. That is, there is an advantage that a preventive and / or therapeutic agent for gastrointestinal dysfunction that can be added to foods and drinks and pharmaceuticals and is excellent in safety can be easily provided.

  The amount of the preventive and / or therapeutic agent for gastrointestinal dysfunction according to the present invention added to a pharmaceutical product or a food or drink varies depending on the form, dosage form, symptom, body weight, use, etc., and is not particularly limited. It can be blended at a content of 0.001 to 100% (w / w) in terms of dry weight of the fermented fungus, preferably 0.01 to 100% (w / w), more preferably 0.1 to 100% (w / w) It can be blended with the content of w).

The daily intake of pharmaceuticals or foods and drinks for preventing and / or treating gastrointestinal dysfunction according to the present invention varies depending on age, symptoms, body weight, use, etc., and is not particularly limited. 0.1 to 10000 mg / kg body weight can be taken in terms of the dry weight of the product, preferably 1 to 400 mg / kg body weight, more preferably 5 to 40 mg / kg body weight.
Moreover, you may use together with the pharmaceutical and foodstuff which have a conventionally known digestive tract dysfunction prevention and / or treatment effect. Specific examples include anticholinergic drugs and dietary fiber-containing foods, but are not limited to these examples.

  The agent for preventing and / or treating gastrointestinal dysfunction according to the present invention can be used in the form of any medicine or food or drink. For example, it is expected to treat and / or prevent various inflammations by direct administration as pharmaceuticals, or by direct intake as special-purpose foods such as foods for specified health use, nutritional functional foods and supplements. In addition, various foods (milk, soft drinks, fermented milk, yogurt, cheese, bread, biscuits, crackers, pizza crusts, prepared milk powder, liquid foods, for the sick, regardless of the form of liquid, paste, solid, powder, etc. Foods, nutritional foods, frozen foods, processed foods, and other commercially available foods).

  The food containing the agent for preventing and / or treating gastrointestinal dysfunction according to the present invention contains water, protein, carbohydrates, lipids, vitamins, minerals, organic acids, organic bases, fruit juices, flavors and the like as main components. Can be used as Examples of the protein include whole milk powder, skim milk powder, partially skim milk powder, casein, whey powder, whey protein, whey protein concentrate, whey protein isolate, α-casein, β-casein, κ-casein, β-lactoglobulin , Α-lactalbumin, lactoferrin, soy protein, chicken egg protein, meat protein and other animal and vegetable proteins, their degradation products; butter, whey minerals, cream, whey, non-protein nitrogen, sialic acid, phospholipid, lactose, etc. And various milk-derived components. It may contain peptides and amino acids such as casein phosphopeptide, arginine and lysine. Examples of the saccharide include saccharides, processed starch (in addition to text phosphorus, soluble starch, British starch, oxidized starch, starch ester, starch ether, etc.), dietary fiber, and the like. Examples of the lipid include animal oils such as lard, fish oil, etc., fractionated oils, hydrogenated oil, transesterified oil, etc .; palm oil, safflower oil, corn oil, rapeseed oil, coconut oil, fractionated oils thereof, Examples include vegetable oils such as hydrogenated oils and transesterified oils. Examples of vitamins include vitamin A, carotene, vitamin B group, vitamin C, vitamin D group, vitamin E, vitamin K group, vitamin P, vitamin Q, niacin, nicotinic acid, pantothenic acid, biotin, inositol, choline. Examples of minerals include calcium, potassium, magnesium, sodium, copper, iron, manganese, zinc, and selenium. Examples of the organic acid include malic acid, citric acid, lactic acid, tartaric acid, erythorbic acid, and the like. These components can be used in combination of two or more, and synthetic products and / or foods containing a large amount thereof may be used. The form of food may be solid or liquid. It may be in the form of a gel.

When the agent for preventing and / or treating gastrointestinal dysfunction according to the present invention is used as a pharmaceutical or a supplement, it can be administered in various forms. Examples of the form include oral administration using tablets, capsules, granules, powders, syrups and the like. These various preparations can be generally used in the pharmaceutical preparation technical field such as excipients, binders, disintegrants, lubricants, flavoring agents, solubilizers, suspension agents, coating agents, etc. as main ingredients according to conventional methods. It can be formulated using known adjuvants. Further, it may contain an appropriate amount of calcium. Further, an appropriate amount of vitamins, minerals, organic acids, sugars, amino acids, peptides, etc. may be added.
It should be noted that all prior art documents cited in the present specification are incorporated herein by reference.

  EXAMPLES Hereinafter, although an Example is given and this invention is demonstrated, this invention is not limited by this.

[Example 1] (Preparation of fermented whey propionate)
(Preparation of medium)
Whey powder (10 w / w%) and protease A “Amano” G (0.07 w / w%, Amano Enzyme) were dissolved in water and subjected to enzymatic degradation at 47 ° C. (pH 6.6) for 2 hours. Thereafter, the enzyme was inactivated by heating at 85 ° C. for 10 minutes. Next, brewer's yeast extract (0.10 w / w%, manufactured by Asahi Breweries) and ammonium sulfate (0.27 w / w%) were added, and the pH was adjusted to 6.7, followed by sterilization at 121 ° C. for 7 minutes.
(Cultivation of propionic acid bacteria)
The prepared medium was inoculated with 2% of P. freudenreichii ET-3 (FERM BP-8115) activation culture solution, anaerobically cultured at 37 ° C for 72 hours in a nitrogen atmosphere, and propionate whey fermentation product (DHNA content) : 0.01 w / w%). In addition, the same culture medium as the above culture medium was used.

[Example 2] (Effect of fermented propionate whey on intestinal smooth muscle)
(Preparation of large intestine specimen)
Six-week-old SD male rats were acclimated for one week and then sacrificed, and the large intestine was removed. Further, about 1 cm of the longitudinal colon of the distal large intestine (about 2 to 3 cm from the anus to the cecum side) was collected, and this was cut out with a width of 3 mm in the longitudinal layer direction (hereinafter also referred to as a colon specimen). Each large intestine specimen was suspended with a 1 g static tension in a Magnus tube filled with Krebs buffer under the following conditions, and a mixed gas of 95% oxygen and 5% carbon dioxide was aerated there. Thereafter, the colon specimen was equilibrated for about 1 hour while changing the Krebs buffer every 15 minutes.
Krebs buffer composition:
Distilled water is added to 1 L of NaCl 6.92 g, KCl 0.35 g, MgSO ₄ .7H ₂ O 0.29 g, KH ₂ PO ₄ 0.16 g, Glucose 2.1 g, CaCl ₂ 0.28 g and NaHCO ₃ 2.1 g.
Temperature of Krebs buffer in Magnus tube: 32 ° C
Amount of Krebs buffer introduced into the Magnus tube: 10 mL

(Preparation of test substance)
Sterilized propionic acid whey fermented product prepared in Example 1 by γ-ray irradiation, added distilled water to the freeze-dried product, and 10w / v% (in terms of lyophilized product) propionic acid whey fermented product. Aqueous solution was prepared. Also, distilled water is added to the lyophilized product of the medium (hereinafter also referred to as unfermented product) before inoculation with the propionic acid bacteria prepared in Example 1, and 10 w / v% (in terms of lyophilized product) is added. A fermented aqueous solution was prepared. These test substance aqueous solutions were used in the following evaluation tests. As a control, distilled water was used.
(Evaluation test of fermented propionate whey)
Replace Krebs buffer and add 10, 30, and 100μL (0.01, 0.03, 0.10w / v% final concentration) of propionic acid whey fermented water solution, unfermented water solution, or distilled water to each Magnus tube, respectively. Then, the tension was measured for 15 minutes and the condition of the muscles was observed. The measurement chart was recorded with a recorder adjusted to move 5 cm per gram of tension on the tension measurement chart. The measurement chart thus obtained is used to observe the peak of tension associated with muscle contraction, from the number of peaks appearing per unit time (minutes) to the contraction frequency (times / minute), and from the peak height (cm) to contract. The intensity (g) calculated and digitized was used for evaluation.

(result)
Table 1 shows the results of the contraction frequency and the contraction strength of each part of the large intestine.

  In the table, * indicates that there is a significant difference of p <0.05 (paired t-test) with respect to the colorectal specimen before the addition of the test substance (the test substance aqueous solution addition amount 0 μL). + And ++ indicate that there is a significant difference of p <0.05, 0.01 (Student's t-test) with respect to the unfermented product.

  The frequency of contraction of the distal large intestine increased in a dose-dependent manner by adding propionate whey fermentation products. When 100 μL of the aqueous propionate whey fermented product solution was added, the contraction frequency was significantly higher (p <0.05, paired t-test) than before the addition. Compared with the unfermented product, when 30 or 100 μL of the aqueous propionate whey fermented product solution was added, the contraction frequency significantly increased at p <0.05 and 0.01 (Student's t-test). On the other hand, none of the unfermented products inoculated with propionic acid bacteria showed an effect of increasing the contraction frequency compared with distilled water or before addition.

  Regarding the shrinkage strength, no change was observed when any test substance was added. That is, it can be said that the fermented whey propionate has neither a contractile force enhancing action nor a contractile force suppressing action. Accordingly, it was found that the fermented propionate whey has an effect of increasing the contraction frequency but does not have an effect of enhancing the contraction force.

[Example 3] (Effects of intestinal smooth muscle at each site of fermented whey propionate)
(Preparation of large intestine specimen)
Six-week-old SD male rats were acclimated for one week and then sacrificed, and the large intestine was removed. In addition, the longitudinal colon of the proximal colon (approximately 1 cm from the cecum side to the anal side), the middle colon (the central part with respect to the entire length of the large intestine), and the distal colon (2 to 3 cm from the anus to the cecum side) Was collected about 1 cm at a time and divided into two in the longitudinal direction (hereinafter also referred to as colon specimen). Each large intestine specimen was suspended with a 1 g static tension in a Magnus tube filled with Krebs buffer under the following conditions, and a mixed gas of 95% oxygen and 5% carbon dioxide was aerated there. Thereafter, the colon specimen was equilibrated for about 1 hour while changing the Krebs buffer every 15 minutes.
Krebs buffer composition:
Distilled water is added to 1 L of NaCl 6.92 g, KCl 0.35 g, MgSO ₄ .7H ₂ O 0.29 g, KH ₂ PO ₄ 0.16 g, Glucose 2.1 g, CaCl ₂ 0.28 g and NaHCO ₃ 2.1 g.
Temperature of Krebs buffer in Magnus tube: 32 ° C
Amount of Krebs buffer introduced into the Magnus tube: 10 mL

(Preparation of test substance)
Sterilized propionic acid whey fermented product prepared in Example 1 by γ-ray irradiation, added distilled water to the freeze-dried product, and 10w / v% (in terms of lyophilized product) propionic acid whey fermented product. Aqueous solution was prepared. This was used as a test substance aqueous solution in the following evaluation tests. As a control, distilled water was used.
(Evaluation test of fermented propionate whey)
Change the Krebs buffer, add 10, 30, and 100 μL of propionate whey fermented water or distilled water (0.01, 0.03, 0.10 w / v% in final concentration) to each Magnus tube, and maintain tension for 15 minutes. Measurements and muscle condition were observed. The measurement chart was recorded with a recorder adjusted to move 5 cm per gram of tension on the tension measurement chart. The measurement chart thus obtained is used to observe the peak of tension associated with muscle contraction, from the number of peaks appearing per unit time (minutes) to the contraction frequency (times / minute), and from the peak height (cm) to contract. The intensity (g) calculated and digitized was used for evaluation. FIG. 1 shows a typical measurement chart when a propionic acid bacteria whey fermentation product is added.

(result)
Table 2 shows the results of the contraction frequency and the contraction strength of each part of the large intestine.

  In the table, ** indicates that the large intestine specimen has a significant difference of p <0.01 (Student's t-test) with respect to the same volume of distilled water.

  The contraction frequency of the proximal colon and the middle colon did not change even when the fermented propionate whey was added, while the contraction frequency of the distal colon was the same as that of the fermented propionate whey. The dose increased in a dose-dependent manner. When 30 μL and 100 μL of the aqueous propionate whey fermented product solution was added, the shrinkage frequency was significantly higher (p <0.01, Student's t-test) than the same volume of distilled water.

  Regarding the contraction strength, no change was observed in the large intestine at any site due to the addition of the fermented propionate whey. That is, it can be said that the fermented whey propionate has neither a contractile force enhancing action nor a contractile force suppressing action. Therefore, it was found that the fermented propionate whey has a contraction frequency increasing action specifically in the distal colon, but has no contractile force enhancing action in any part.

Example 4 (Efficacy of Propionic Acid Whey Fermented Product in Irritable Bowel Syndrome Constipation Type Patient)
(Method)
A double blind crossover test was conducted on 12 patients with irritable bowel syndrome constipation (3 men, 9 women: age 27-77). Six of the subjects selected at random were sterilized by heating the propionic acid bacteria whey fermented product produced by the method of Example 1 and then dried (active) containing 0.2 g / 3 tablets. For 4 weeks (28 days), 3 tablets were orally ingested 3 times a day for a total of 9 tablets per day. The other 6 patients were orally ingested 3 tablets per day for 4 weeks (28 days) containing lyophilized unfermented whey powder reduced solution instead of the propionate whey fermented product [placebo] Early intake period]. Over the next 4 weeks (28 days), all 12 subjects stopped taking the tablets [intake stop period]. Further, over the next 4 weeks (28 days), 3 tablets were orally ingested 3 times a day for a total of 9 tablets per day. At this time, those who took active last time took placebo, and those who took last placebo took active [late intake period].

(Evaluation methods)
(1) Symptom Questionnaire Questionnaire regarding symptoms was completed every day during the tablet intake period. FIG. 2 shows a questionnaire to be entered on each day. The question item here relates to the defecation status. Specific questions include the number of defecations, the nature of the stool, the intensity of abdominal pain, the feeling of residual stool and the degree of breathing during defecation, and the quality of the abdominal state. The stool properties were scored with the pictures and descriptions shown in FIG. In addition, the intensity of abdominal pain (abdominal pain is present), degree of abdominal fullness (abdominal fullness), feeling of residual stool and degree of stool during defecation (reducing stool sensation and requiring stool during defecation), abdomen The quality of the condition (the total score of the tummy of today) was expressed using the visual analogue scale. The result of visual analogue scale was measured from “not” or “very bad” at one end of the scale to the mark entered by the subject, and this length was divided by the total length of the scale. The value was calculated and derived. After collecting the questionnaire, the placebo and activity are summarized by intake period from 1 to 28 days and from 15 to 28 days, and the average value, standard deviation, and P value (placebo vs. active, Student's t-test) for each item Calculated.
In addition, the questionnaire shown in FIG. 3 was completed on the last day of the first period intake period and the last day of the second period intake period. The question items here relate to general abdominal conditions. Specific questions include a comparison of the abdominal state before the intake period (general improvement) and a comparison of the abdominal state when the other tablets were taken last time (comparison between the previous period and the latter period). These evaluations were selected one by one from those shown in FIG. The overall improvement was evaluated according to a five-point scale: "Improved (very effective)", "Improved (effective)", "I didn't change (immutable)", "I got worse", and "I got very bad" Consists of. After collecting the questionnaire, the number of responses at each stage was calculated for each placebo and active, and the proportion of respondents who responded markedly or effectively was calculated as the effective rate (%). Statistical analysis was performed by cumulative chi-square test. In addition, the comparison between the first half and the second half (before / after comparison) consists of a three-step evaluation: “the first half was better”, “not changed”, and “the second half was better”. After collecting the questionnaire, the number of responses at each stage was calculated for each placebo and active.

(2) SF-36 questionnaire
The SF-36 (MOS Short-Form 36-Item Health Survey) questionnaire is known as a comprehensive measure with scientific reliability and validity for measuring health-related quality of life. It is the most popular questionnaire in the world to measure health because it is readily available, simple and useful, and already has enough data. Specifically, QOL is measured from 36 questions in the following 8 areas (subscales), and the QOL of all people is comprehensively evaluated.
1) Physical function [PF]
2) Daily role function (body) [RP]
3) Body pain [BP]
4) Overall health [GH]
5) Vitality [VT]
6) Social life function [SF]
7) Daily role (spirit) [RE]
8) Mental health [MH]
The inventors conducted tests according to the description of Shunichi Fukuhara and Yoshimi Suzuka “SF-36v2 ^TM Japanese Version Manual”, Healthcare Evaluation and Research Organization, 2004.
The SF-36 questionnaire was completed before the first period and the last day of the first period and before the second period and the last day of the second period. Further, the questions in the above 1) to 8) areas were converted into scores by scoring (NBS: Norm-based Scoring) based on national standard values and scored. This score is a recalculation of the 8 subscale scores in the range from 0 to 100 so that the national standard value for the entire Japanese population is 50 points and the standard deviation is 10 points. is there. The national standard value is the average score of SF-36 obtained from a nationwide survey that was sampled to be the same as the distribution of national gender, age, region, and city size.
In this study, the number of cases in which the score was improved before and after each intake period, the number of cases in which no change was observed, and the number of cases in which exacerbations were observed were obtained. In addition, the change in each score before and after each intake period was calculated, and the effect of taking active or placebo was evaluated.

(result)
(1) The results of the questionnaire regarding symptoms are shown in Table 3 and Table 4.

  As shown in Table 3, the mean value (mean), standard deviation (SD) and P value (p value: Student's t-test) of each evaluation value from the intake period 1 to 28 days and 15 to 28 days are obtained. Compared with placebo and active. In Table 3, # indicates p <0.10, * indicates p <0.05, and ** indicates p <0.01. On days 1 to 28 after ingestion, there was an active and significant improvement in comparison with placebo at a risk rate of 5% for the feeling of residual stool and the overall score for tummy. In addition, the number of bowel movements showed an improvement trend (p <0.10: Student's t-test). Furthermore, on days 15 to 28 after ingestion, there was an active and significant improvement in comparison with placebo at a risk rate of 1% and 5%, respectively, in the residual score and the overall score of tummy (Student's t-test). In addition, an improvement trend (p <0.10: Student's t-test) was observed in the number of defecations and abdominal fullness.

As shown in Table 4, the overall improvement rate was 25% in the placebo intake and 67% in the active intake, and the active group showed an improvement tendency between both groups (p <0.10: cumulative χ2 Power test).
In addition, the number of respondents who answered that active intake was better than placebo intake was 8 out of 12 cases, the number of respondents who said that placebo was better was 3 cases, and the number of cases who answered that there was no difference was 1 It was an example. In addition, no significant difference was observed between late intake in the first half of the period.

(2) The results of the SF-36 questionnaire are shown in FIGS.
FIG. 4 shows a comparison of scores before and after active intake in the upper row, and a comparison of scores before and after placebo intake in the lower row, in the ratio of the number of cases. In the active group, there were many cases where the overall score improved compared to the placebo group, and there were many cases where the physical pain and overall health were particularly improved.
FIG. 5 shows the change in score before and after ingestion. Specifically, for each placebo and active, a value obtained by subtracting the score before ingestion from the score after ingestion was calculated, and this was evaluated as a change in score. Overall, active intake showed an increase in score, but there were items that decreased in the placebo group. Regarding body pain [BP], the score was significantly increased (p <0.05, Student's t-test) compared to placebo. Therefore, the results showed that the preventive and / or therapeutic agent for gastrointestinal dysfunction according to the present invention improves physical function. Along with this, vitality [VT] and social life function [SF], which showed a tendency to exacerbate when placebo was ingested, showed an improvement trend due to active ingestion. Therefore, the results showed that the preventive and / or therapeutic agent for gastrointestinal dysfunction according to the present invention improves mental function. From these results, it was found that the intake of the preventive and / or therapeutic agent for gastrointestinal dysfunction according to the present invention improves the QOL of patients with irritable bowel syndrome from both physical and mental functions.
[Example 5] (Effect of propionate sodium salt and acetate sodium salt on intestinal smooth muscle in fermented whey propionate)
The propionic acid bacterial whey fermentation product produced in Example 1 and tested in Examples 2 and 3 contains propionic acid and acetic acid at a concentration of 0.1 mol / L, respectively. It was examined in an experimental system according to Example 2 whether these organic acids affect the test results.

(Preparation of large intestine specimen)
Seven-week-old SD male rats were acclimated for one week and then sacrificed, and the large intestine was removed. Further, about 1 cm of the longitudinal colon of the distal large intestine (2 to 3 cm from the anus to the cecum side) was collected and divided into two in the longitudinal direction. (Hereafter, this is also referred to as a colon specimen). Each large intestine specimen was suspended with a 1 g static tension in a Magnus tube filled with Krebs buffer under the following conditions, and a mixed gas of 95% oxygen and 5% carbon dioxide was aerated there. Thereafter, the colon specimen was equilibrated for about 1 hour while changing the Krebs buffer every 15 minutes.
Krebs buffer composition:
Distilled water is added to 1 L of NaCl 6.92 g, KCl 0.35 g, MgSO ₄ .7H ₂ O 0.29 g, KH ₂ PO ₄ 0.16 g, Glucose 2.1 g, CaCl ₂ 0.28 g and NaHCO ₃ 2.1 g.
Temperature of Krebs buffer in Magnus tube: 32 ° C
Amount of Krebs buffer introduced into the Magnus tube: 10 mL

(Preparation of test substance)
Distilled water was added to sodium propionate and sodium acetate to prepare 0.1 mol / L sodium propionate aqueous solution and 0.1 mol / L sodium acetate aqueous solution, which are the concentrations contained in the propionate bacterial whey fermentation product. . These were used in the following evaluation tests as test substance aqueous solutions. As a control, distilled water was used.
[Evaluation test of fermented propionic acid bacteria whey]
The Krebs buffer was changed, and 10, 30 and 100 μL of 0.1 M sodium propionate aqueous solution, 0.1 M sodium acetate aqueous solution, or distilled water were added to each Magnus tube, respectively, and the tension measurement and muscle condition were observed for 15 minutes. . The measurement chart was recorded with a recorder adjusted to move 5 cm per gram of tension on the tension measurement chart. The measurement chart thus obtained is used to observe the peak of tension associated with muscle contraction, from the number of peaks appearing per unit time (minutes) to the contraction frequency (times / minute), and from the peak height (cm) to contract. The intensity (g) calculated and digitized was used for evaluation. About the result obtained in this way, the comparison between groups was further tested for significance by Student's t-test.

(result)
Table 5 shows the results of the contraction frequency and the contraction strength.

  Regarding the contraction frequency, no change was observed even when any test substance was added. That is, it can be said that the propionic acid sodium salt and sodium acetate contained in the propionic acid bacteria whey fermentation product have neither a contraction frequency enhancing action nor a contraction frequency suppressing action.

  Regarding the shrinkage strength, no change was observed when any test substance was added. That is, it can be said that the propionic acid sodium salt and sodium acetate contained in the propionic acid bacteria whey fermented product have neither a contractile force enhancing action nor a contractile force suppressing action.

Since it has an action to prevent and / or treat gastrointestinal dysfunction, it can be applied as a pharmaceutical or a food or drink having the same function.

Claims (10)

  A prophylactic and / or therapeutic agent for gastrointestinal dysfunction comprising a fermented propionic acid bacterium and / or a processed product thereof as an active ingredient.   The agent for preventing and / or treating gastrointestinal dysfunction according to claim 1, wherein the propionic acid bacterium belongs to the genus Propionibacterium.   The agent for preventing and / or treating gastrointestinal dysfunction according to claim 2, wherein the bacterium belonging to the genus Propionibacterium is Propionibacterium freudenreichii.   The agent for preventing and / or treating gastrointestinal dysfunction according to claim 3, wherein the Propionibacterium freudenreichii is Propionibacterium freudenreichii ET-3 (FERM BP-8115).   The preventive and / or therapeutic agent for gastrointestinal dysfunction according to any one of claims 1 to 4, wherein the propionic acid bacteria fermented product is a propionic acid bacteria whey fermented product.   6. Gastrointestinal dysfunction prevention according to any one of claims 1 to 5, wherein the gastrointestinal dysfunction is one or a combination of a group consisting of irritable bowel syndrome or functional constipation. Or a therapeutic agent.   A food for preventing and / or treating gastrointestinal dysfunction, comprising the agent for preventing and / or treating gastrointestinal dysfunction according to any one of claims 1 to 6.   Use of the fermentation product of propionic acid bacteria for the manufacture of a preventive and / or therapeutic agent for gastrointestinal dysfunction according to any one of claims 1 to 6.   Use of the fermentation product of propionic acid bacteria for the manufacture of a food for preventing and / or treating gastrointestinal dysfunction according to claim 7.   A method for preventing and / or treating gastrointestinal dysfunction, comprising administering a fermented propionic acid bacterium and / or a processed product thereof.

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